AIDS Treatment News
March 6, 1998

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Drug Interactions

Resources for Patients and
Professionals

by John S. James

Drug interactions are common in HIV treatment. But
modern medical practice, with pressures to hurry due to
cost control, may not leave enough time for physicians
to make sure that they know about everything their
patients are taking, and counsel them on potential
risks. Not all drug interactions are harmful; some
treatment combinations are designed to use interactions,
and others can be adjusted to compensate for them. But
patients may want to check their regimens to be aware of
potential problems that they should bring to their
doctor's attention.

Here are two AIDS-related drug interaction resources
that are readily available. The first is written
primarily for health care professionals, the other for
patients.

This new one-hour CME (continuing medical education)
module, written for physicians, pharmacists, and nurses
but available to anyone through the World Wide Web,
provides background on drug interactions as well as
lists of what to watch out for. You can also submit your
own regimen for an immediate computerized report on
known potential interactions.

Most drug interactions fall into one or more of several
classes, making them somewhat more predictable than
might be expected. The background section of this
training module -- "How Drugs Interact: What You Need to
Know" explains how most drugs are metabolized, and lists
the five most important kinds of pharmacokinetic
interactions, in which one drug affects the
concentration of another ("inhibition of metabolism;
induction of metabolism; altered drug absorption;
inhibition of renal excretion; and displacement from
plasma protein binding sites"). There are also
pharmacodynamic interactions ("synergism or antagonism
of drug effects, without alterations in the
concentrations of either drug"). This section also
describes the cytochrome P450 system, an important part
of one of the two major ways the liver metabolizes
drugs.

The next section, on questions health care providers
need to ask themselves and their patients, lists
practical issues which can be overlooked, such as:

The next section, "What Drugs are Most Likely to Be
Involved in Drug Interactions," is organized around "the
'red flag' list" of five different groups of drugs that
need special attention: "P450 inducers, P450 inhibitors,
metabolized drugs with narrow therapeutic indices,
renally cleared drugs with narrow therapeutic indices,
drugs with specific requirements for absorption."
Alternatives are suggested for many of the medications
which can be problematic.

There is also a drug-food interaction table, a sample
daily dosing schedule, and links to other Web sites with
more information.

This drug interaction guide is published by HealthCare
Communications Group, and is available at
http://www.healthcg.com. The entire course can be
printed easily, so if you do not have online access
yourself, someone else could print the material for you.

Project Inform's Drug Interactions Fact Sheet,
by Ben Cheng

This simpler drug interaction guide has one page of
introduction written for patients, and 17 pages of
drug-drug interactions listed alphabetically by generic
drug names. There is also a short glossary of terms used
in describing the side effects. The introduction
includes practical measures, such as the "brown bag
medicine checkup -- each time you see your health care
provider, put all your medications, including over-the-counter and complementary products, in a bag and have
your physician conduct a personalized review of your
medicine for safety, appropriateness, compatibility, and
instructions for use."

You can obtain a copy from Project Inform. Call the
hotline, 800-822-7422 or 415-558-9051, 9 a.m. to 5 p.m.
Pacific time Monday through Saturday -- or write to:

Project Inform
205 13th St., #2001
San Francisco, CA
94103

or get the information directly from
http://www.projinf.org. The latest version, dated
February 1998, will include information from the
Retroviruses conference (Chicago, February 1-5).

Medical Marijuana Update

by John S. James

New Threat to California Patients' Access

Thousands of patients who urgently need marijuana for
major medical problems are again facing a possible
cutoff of their supplies from the buyers' clubs. The
immediate problem is that on February 25 the California
Supreme Court refused to review a decision of a
California appeals court against the clubs. In December
the appeals court had ruled on a 2-1 vote that a patient
cannot designate a club as "primary caregiver" under
Proposition 215, the voter-approved initiative to allow
medical marijuana under California law. This ruling
occurred in the case of a single club -- the Cannabis
Cultivators Club run by Dennis Peron -- but has now become
binding on lower courts throughout California. There are
about 20 marijuana buyers' clubs in the state, and all
are now seriously threatened.

The appeals court decision means that patients can
legally obtain marijuana only by growing it themselves,
or having their primary caregiver grow it for them; they
can reimburse their caregiver for expenses. There is no
legal way to obtain the seeds, however. And there are
thousands of patients with wasting syndrome, or using
chemotherapy, or with other serious conditions, who
could not wait for the six months required to grow a
flowering plant. Many could not grow their own due to
their health status, or their living situation, due to
the threat of eviction or arrest. In much of California
police routinely arrest and charge patients for growing
marijuana, despite medical documentation, following
instructions from California Attorney General Dan
Lungren, the major opponent of medical marijuana in the
state.

The patients affected are those for whom no other
treatment has worked, since doctors have been threatened
and are unlikely to provide medical documentation unless
there is no workable alternative. While it may seem easy
to obtain marijuana illegally for recreational use,
patients who need it medically are usually not part of
that culture, and may be unable to find someone who
would risk felony charges by providing it to them.

No one knows what will happen. The Cannabis Cultivators
Club has said it will remain open, not to sell marijuana
but to provide help in cultivation; it could face a raid
or a civil injunction. There is widespread concern that
closing the remaining clubs will create a medical
emergency, as patients who urgently need the drug are
forced to seek it from the worst source of supply,
strangers on the street.

Meanwhile, Peron and five other cannabis clubs filed a
legal brief responding to separate Federal action
against them. The 34-page brief, submitted on February
27, is available at http://www.marijuana.org. (Several
legal filings and court decisions on this Web site are
useful for journalists and others seeking background on
these issues.)

See also The New York Times, "Moving to Semantical High
Ground: California Marijuana Club Stands Firm Against
Court Rulings," March 1, 1998, page 14 of the national
edition. On the human impact, see the San Francisco
Examiner, "Wracked by Pain, but Defiant," March 3,
1998, page 1.

Peron Qualifies As Republican Candidate for Governor

Marijuana activist Dennis Peron has officially qualified
as a candidate for governor of California, running
against California Attorney General Dan Lungren in the
Republican primary in June. This election will be the
first one under California's new "open primary"
system -- meaning that any voter can vote in the
Republican primary, even if they are registered
Democrats or in other parties, or are independent (they
can vote in only one party's primary, however). Peron
could obtain a significant vote as a protest against
Lungren.

For bumper stickers ("Hope, Empowerment, Compassion -- For
A Better World"), buttons, literature, and other
material, contact the Peron for Governor campaign,
415-621-3986, or see http://www.marijuana.org.

New Scientist Publishes Major Marijuana Report,
Exposes Suppression of WHO Study Findings

"Marijuana Special Report," published February 21 in New
Scientist, includes 10 articles on marijuana. This
report, a backgrounder not focused on medical use, is
available at http://marijuana.newscientist.com/.

One of the articles, "High Anxieties: What the WHO
Doesn't Want You to Know About Cannabis," revealed that
a major World Health Organization report on marijuana,
published last December, was supposed to contain an
analysis showing that this drug is less harmful than
alcohol or tobacco. This section was excluded after
pressure from drug-war officials in the U.S. and the UN.

The suppressed analysis, which compared different kinds
of harm caused by the different drugs, stated that the
comparisons were "not to promote one drug over another
but rather to minimize the double standards that have
operated in appraising the health effects of cannabis."
We do not know if the censored text has become public.

Apparently no U.S. newspaper reported this story,
although it was carried in Reuters and published in
newspapers elsewhere.

Comment

What is striking about the politics of medical marijuana
is the difficulty of reaching a workable compromise in
Sacramento or Washington, even when many peoples' health
and lives are at stake. No one doubts that marijuana is
far less dangerous than morphine, and certainly less
subject to abuse; yet morphine is accepted as medicine,
while medical marijuana is the target of a government
crusade. Public opinion throughout the nation strongly
supports allowing patients to use marijuana for relief
or treatment of major illness; and many politicians
campaign around the general principle of reducing
government interference so that people can make the
decisions which work for them. But on this treatment
issue, freedom and compassion have been forgotten, and
the machinery of government has been largely controlled
by those with other ideas.

Medical Advances with International Impact

by John S. James

Some recent advances can be particularly important for
developing countries where about 90% of people with HIV
live. Public support will be will be crucial in
improving treatment access for more people. These issues
are becoming more prominent during preparations for the
12th World AIDS Conference, June 28 - July 3 in Geneva.

Simplified AZT Regimen Cuts Maternal-Infant Transmission
in Half

On February 18 the U.S. Centers for Disease Control and
the Ministry of Public Health of Thailand announced that
a short course of AZT can greatly reduce the risk of
transmission of HIV from mother to infant. The
simplified regimen used AZT orally twice a day for the
mother, starting at week 36 of pregnancy and continuing
through labor. The drug was not given to the infant. The
women in this trial were not breastfeeding.

This result means that we now know that a regimen
suitable for developing countries can prevent maternal
transmission of HIV. The next step is to push to make
the treatment available to all HIV-positive pregnant
women who want it -- as well as supporting the ongoing
research to find better prevention methods, perhaps
using more than one drug.

The AZT regimen now used in rich countries to prevent
maternal transmission has been unworkable in much of the
world, mostly but not entirely because of the cost. The
conventional treatment starts much earlier, at week 26
of pregnancy -- but in many countries women do not come in
for care until shortly before delivery. The women take
AZT five times a day for the rest of the pregnancy, and
then intravenously during labor; in addition, the infant
receives AZT orally for two months. The new regimen can
be started late, avoids all intravenous treatment, uses
twice daily dosing, and requires much less of the drug.
However it was not as effective as the more extensive
regimen, reducing transmission about 50% (from 18.6%
without AZT to 9.2% with AZT in the Thailand trial), vs.
almost 70% (25% without AZT to 8% with AZT, in the
earlier trial in the U.S.).

The new report also ends the divisive dispute on use of
placebos in trials to reduce transmission in developing
countries. From now on the placebo arms will be dropped
or switched to the short-course AZT regimen, now that it
is known to work.

Mark Harrington of the Treatment Action Group called on
Glaxo Wellcome to "make AZT available to developing
countries for a substantially reduced price, or give the
drug away for free, as Merck did with its drug for
African river-blindness. Over 500,000 children are born
with HIV each year. Short-course AZT could prevent
infection in at least half of these cases, saving
millions of lives in the next few years."

UNAIDS, which coordinated the international research
effort which included the Thailand trial, will hold a
meeting of interested governments and agencies in Geneva
at the end of March, "to find ways of rapidly and
effectively implementing the results of this and other
trials into public health policy as they become known."

Tuberculosis Prevention: Faster Two-Drug Regimen Found
Effective

A trial in almost 1600 people with HIV found that a
two-month regimen with two drugs (rifampin and
pyrazinamide) was as effective as the conventional
one-year regimen of isoniazid in preventing development
of active tuberculosis, in persons who were known to be
TB-infected as determined by a positive skin test. The
two-month regimen is easier and less expensive to
administer; it also seemed to have better survival (5.8
deaths per 100 patient years, vs. 6.7), although this
difference was not enough to be statistically
significant, meaning that it could have occurred by
chance. The two-month regimen is likely to be preferred
in the U.S., but could be more important in developing
countries where preventive treatment has not been widely
used so far because of cost. HIV can greatly accelerate
the development of tuberculosis, which causes about a
third of AIDS-related deaths in the world.

About 70% of the volunteers in this study were in the
U.S., enrolled through government research programs.
Others were in Haiti, Brazil, and Mexico. The results
were reported at the 5th Conference on Retroviruses and
Opportunistic Infections (F Gordin and others, A
Randomized Trial of 2 Months of Rifampin (RIF) and
Pyrazinamide (PZA) Versus 12 Months of Isoniazid (INH)
for the Prevention of Tuberculosis in HIV-Positive(+),
PPD+ Patients (pts) (late breaker abstract #LB5].)

Dried blood spots -- a well-known method of preserving
blood samples for certain tests -- may be useful in some
cases for measuring HIV viral load. The advantage is
that the samples do not need refrigeration, nor require
a centrifuge or other special equipment or supplies that
are unavailable in many settings. Also, much less blood
is used, an advantage particularly for infants. Three
studies on dried blood spots were presented at the 5th
Conference on Retroviruses and Opportunistic Infections,
Chicago, February 1-5, 1998.

Viral load testing can be used to diagnose many
HIV-infected infants in the first days or week of life,
so that treatment can be started only for those who need
it. The standard antibody test for HIV infection will
not work until later, because all infants of
HIV-infected women will test positive due to the
mother's antibodies. One study suggested that samples
can be pooled when screening for HIV infection, greatly
reducing the cost of the testing, which could help in
making medical care available to persons who otherwise
would not receive it.

The three new studies are:

S Cassol and others, Dried Blood Spots (DBS) for
Monitoring HIV-1 RNA Load in Neonates and Infants
[abstract #315]. This study used two different viral
load test kits, the Roche Monitor PCR vs. NASBA, to
measure viral load in stored dried blood spots, and
compared the results to those of conventional viral load
measurements using liquid plasma, which had been run
earlier for the same infants. It concluded that "HIV-1
RNA recovery in DBS is feasible, highly reproducible,
and compares favorably with conventional liquid plasma
measurement, making it suitable for use in large-scale
international field trials."

AM Comeau and others, Use of Microsample Dried Blood
Spot RNA Assays for Diagnosis of Pediatric HIV in the
First Week of Life [abstract # 530]. Here the same team
reported on tests of dried blood spots to diagnose HIV
infection early after birth. The researchers concluded
that "with slight modifications, RNA kits designed for
viral load determinations can be used reliably on
microsample DBS to detect the presence of HIV early in
life."

AM Comeau and others, Quality-Controlled Pooling
Strategies for Nucleic-Acid Based HIV Screening: Using
PCR as a Primary Screen on Dried Blood Spot Specimens in
Population Studies [abstract #318].

This study looked at pooling part of the material from
dried blood spot samples, to reduce the labor and the
number of test kits needed to screen for HIV infection.
In this case, pooling means combining several samples
for an initial test; if the batch tests negative, then
all the samples are known to be negative, and if the
batch tests positive, then all samples in that batch
must be tested individually. This procedure, applied to
stored blood samples from newborns in this research
project, reduced the number of tests to less than a
third of what would otherwise have been required.

Oral Contraceptive / Nevirapine Interaction Trial

New York and San Francisco

A six-week pharmacokinetic trial to see if the oral
contraceptive Ortho Novum affects levels of the
antiretroviral nevirapine, or vice versa, is now
recruiting women in New York and San Francisco.

Participants must have an undetectable viral load, CD4
count over 100, have no active infection, and be on a
stable antiretroviral regimen (which cannot include
current use of ritonavir or delavirdine, although
previous use may be OK). There are additional entry
criteria.

At the San Francisco site, participants will be
compensated $500 on completion of the study; free
parking will be provided, and transportation and child
care costs can be reimbursed. At the New York site,
volunteers will be compensated similarly. Some time in
the clinic will be required for blood tests.

This may be the first trial for drug interactions
between antiretrovirals and oral contraceptives.

For more information, in San Francisco call Sal
Iacopelli, 415- 353-6215. In New York, call Carsandra
Diggs or Steve Nowling at the Clinical Trials Unit at
Beth Israel Medical Center, 212- 420-4519.

IL-2 Without Antiretroviral Therapy

Trial Near Washington, D.C.

The National Institute of Allergy and Infectious
Diseases is recruiting persons with a CD4 count over 350
who do not plan to start antiretroviral therapy in the
next year, for a phase II trial to determine the safety
and efficacy of subcutaneous IL-2 without
antiretrovirals for persons with relatively early HIV
infection. They must have no antiretrovirals for six
weeks before entering the trial, and "willingness to
remain off antiretroviral therapy for 12 months or until
a protocol- defined recommendation or required change is
determined."

The only trial site is at the National Institutes of
Health campus, in Bethesda, Maryland near Washington
D.C.

FDA Publishes Conflict of Interest Rules for Clinical Trials

by John S. James

On February 2 the FDA published rules which, when they
become effective in February 1999, will require
disclosure of certain financial arrangements between
pharmaceutical companies and certain clinical
investigators, when a drug is submitted for marketing
approval. Most of this information will come from the
companies, since they already know what their financial
arrangements with their investigators are; it appears
that individual researchers will only need to disclose
stock ownership in the sponsoring company. The FDA
estimates that only one to ten percent of companies
submitting applications for approval of drugs or devices
will need to submit disclosures for one or more of their
investigators. The FDA will decide case by case whether
the information will be made public. The disclosure
requirement applies to "any listed or identified
investigator or subinvestigator who is directly
involved in the evaluation of research subjects," and to
immediate family members.

The purpose of the new rule is to prevent bias in safety
and efficacy studies of drugs and medical devices. We
note it here for three reasons:

Clinical researchers may want to avoid the kinds of
financial relationships which are likely to raise a red
flag at the FDA -- particularly "compensation made to the
clinical investigator in which the value of the
compensation could be affected by the study outcome; a
proprietary interest by the investigator in the tested
product, such as a patent; a significant equity interest
in the sponsor of the covered study; or significant
payments by the sponsor of the covered study of other
sorts, such as a grant to fund ongoing research,
compensation in the form of equipment, or retainers for
ongoing consultation or honoraria." Disclosure will be
required for stock ownership over $50,000 in the
sponsoring company, or other payments over $25,000. The
new rule does not prohibit any form of compensation; but
companies and researchers may want to avoid those which
will require disclosure, because they will subject the
company's new drug application to extra scrutiny.

Persons investigating conflict of interest in medical
research can find detailed background in the 19,000-word
FDA publication, which includes in-depth discussion of
why certain provisions were and were not included in the
new rule, answers objections from industry, and
comparison of this rule with other government disclosure
requirements.

Even though the February 2 publication is a "final
rule," certain parts are still open for public comment
until April 3. After that, the FDA will submit the rule
to the OMB (Office of Management and the Budget) for
final approval, and there will be an additional period
for public comment to OMB.

The published regulation appears in the Federal Register, February 2, 1998, volume 63 number 021, 63 FR
5233. If you are doing a computer search of the Federal Register, we found that the phrase "disclosable
financial" was a useful search term for finding this
publications. You can search the Federal Register
without charge through the Web site of the National
Archives and Records Administration,
http://www.access.gpo.gov/nara/.

ISSN # 1052-4207

Copyright 1998 by John S. James. Permission granted for noncommercial reproduction, provided that our address
and phone number are included if more than short quotations are used.

A note from TheBody.com: The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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